status espileptico

1. Epilepsia, 48(9):1652–1663, 2007
Blackwell Publishing, Inc.
C 2007 International League Against Epilepsy
The Epidemiology of Convulsive Status Epilepticus
in Children: A Critical Review
∗†‡Miquel Raspall-Chaure, ∗§Richard F. M. Chin, ∗†‡Brian G. Neville, §Helen Bedford,
and ∗†‡¶Rod C. Scott
∗Neurosciences Unit, UCL – Institute of Child Health, London; †Epilepsy Unit, Great Ormond Street Hospital for Children NHS
Trust, London; ‡The National Centre for Young People with Epilepsy, Lingfield; §Centre for Paediatric Epidemiology and
Biostatistics, UCL – Institute of Child Health, London; and ¶Radiology and Physics Unit, UCL – Institute of Child Health, London,
United Kingdom
Summary: There is ongoing debate regarding the most
appropriate definition of status epilepticus. This depends upon
the research question being asked. Based on the most widely
used “30 min definition,” the incidence of childhood convulsive
status epilepticus (CSE) in developed countries is approximately
20/100,000/year, but will vary depending, among others, on
socioeconomic and ethnic characteristics of the population. Age
is a main determinant of the epidemiology of CSE and, even
within the pediatric population there are substantial differences
between older and younger children in terms of incidence,
etiology, and frequency of prior neurological abnormalities or
prior seizures. Overall, incidence is highest during the first year
of life, febrile CSE is the single most common cause, around
40% of children will have previous neurological abnormalities
and less than 15% will have a prior history of epilepsy. Outcome
is mainly a function of etiology. However, the causative role of
CSE itself on mesial temporal sclerosis and subsequent epilepsy
or the influence of age, duration, or treatment on outcome of
CSE remains largely unknown. Future studies should aim at
clarifying these issues and identifying specific ethnic, genetic,
or socioeconomic factors associated with CSE to pinpoint
potential targets for its primary and secondary prevention. Key
Words: Etiology—Children—Epilepsy—Epidemiology—Eth-
nicity—Incidence—Outcome—Mortality—Morbidity—Socio-
economic status—Status epilepticus.
Epidemiological studies investigate how many people
developadiseaseorconditionovertime,describethenatu-
ral history and outcomes of the disease, the characteristics
of those affected, and may generate hypotheses about the
cause of the disease. These results provide essential data
for the prevention, control, and treatment of the condition
under study (Grimes and Schulz, 2002).
There are many shortcomings in the understanding of
the epidemiology of status epilepticus in childhood pri-
marily related to methodological problems, which include
inappropriate study design, case definition, ascertainment,
classification of etiologies, and techniques used in assess-
ing outcome during follow-up (Hauser, 1983). In addition
to these concerns, status epilepticus is an event that is
Accepted April 28, 2007.
Address correspondence and reprint requests to Dr. Rod C. Scott,
Senior Lecturer in Paediatric Neurosciences and Honorary Consultant
Paediatric Neurologist, Neurosciences Unit, UCL – Institute of Child
Health, The Wolfson Centre, Mecklenburgh Square, London WC1 N
2AP, United Kingdom. E-mail: r.scott@ich.ucl.ac.uk
doi: 10.1111/j.1528-1167.2007.01175.x
All authors contributed equally to the preparation of the review.
related to an underlying condition (known or unknown)
and so has to be viewed as part of the natural history of
several conditions that have their own epidemiological is-
sues. This adds a layer of complexity to understand the
epidemiology of status epilepticus.
Age is a fundamental determinant of the epidemiol-
ogy of status epilepticus and many of the epidemiologi-
cal aspects of status epilepticus differ between adults and
children. Even within the pediatric population, there are
substantial differences between older and younger chil-
dren in terms of incidence, etiology, frequency of prior
neurological abnormalities, and prior history of unpro-
voked seizures (Shinnar et al., 1997). Most epidemiolog-
ical studies on status epilepticus have been primarily or
exclusively based on adult populations and may not reflect
a reliable characterization of status epilepticus in children
(Chin et al., 2004a).
Statusepilepticusmaybeclassifiedasconvulsive(CSE)
or nonconvulsive (non-CSE). CSE is the most common
form of status epilepticus, but its relative frequency is dif-
ficult to document because the various types of status are
1652

2. EPIDEMIOLOGY OF STATUS EPILEPTICUS 1653
not specified separately in most series. Despite contro-
versies in diagnostic criteria for non-CSE, it is accepted
that EEG is mandatory for the diagnosis (Brenner, 2002;
Walker et al., 2005) and the true incidence of non-CSE
(and status epilepticus in general) will remain elusive un-
til EEG testing of all children with suspected non-CSE in
the emergency department is widespread practice.
Thus, epidemiology of CSE in children will be the focus
of this review. Neonatal seizures will not be considered as
the specific etiologies and the definitions of status epilepti-
cus in this setting deserves detailed separate consideration.
The available data on the incidence, etiology, seizure char-
acteristics, and outcome in non-neonatal childhood CSE
will be discussed and suggestions for future research will
be made.
THE DEFINITION ISSUE
Epidemiological studies should use explicit definitions
of the condition of interest. Debate is ongoing regarding
the most appropriate definition of status epilepticus, which
is reflected in the inconsistent use of the term in published
studies on the subject. The most common criterion for
the diagnosis of status epilepticus has been the duration
of seizure activity, which has varied considerably. Studies
from the 1970s used a 1-h-duration criteria (Aicardi and
Chevrie, 1970; Fujiwara et al., 1979). Subsequently, most
studies, including all epidemiological studies, have used
a 30-min-duration criteria. The justification for this dura-
tion is that this is the time at which status epilepticus may
become self-sustaining, pharmacoresistance may have de-
veloped, and seizure-induced neuronal injury may take
place (Chen and Wasterlain, 2006). On its last proposal of
terminology, the International League Against Epilepsy
(ILAE) defined status epilepticus as “a seizure that shows
noclinicalsignsofarrestingafteradurationencompassing
the great majority of seizures of that type in most patients
or recurrentseizureswithoutinterictalresumptionofbase-
line central nervous system function,” but did not set a
FIG. 1. Duration of seizure activity against key time periods in the natural history of a prolonged seizure.
temporal criterion as had previously been the case (Com-
mission on Epidemiology and Prognosis, 1993; Blume
et al., 2001; Engel, 2001). This definition, which may be
judged as somewhat ambiguous, is in more accordance
with recently proposed “operational” definitions that aim
to define the time when patients should be treated as if
they were in established status epilepticus; this includes
seizure durations as low as 5 min (Lowenstein et al., 1999)
(Fig. 1).
There is probably a need for different definitions, hav-
ing different specifications for duration of seizures or re-
covery of consciousness, which are tailored to a partic-
ular research question. Operational definitions serve as
much better guides for treatment and should be those used
in clinical trials. In contrast, there are no clear reasons
to modify the “traditional” 30-min-duration definition to
evaluate the incidence and outcome of CSE until a better
understanding of the pathophysiological and prognostic
determinants of CSE has been reached.
THE CLASSIFICATION ISSUE
There is good evidence from epidemiological studies
and clinical series that etiology is an important determi-
nant of the outcome of patients with CSE, and it is there-
fore important to identify and classify the causes of CSE
accurately (Raspall-Chaure et al., 2006).
Inchildren,asignificantproportionofCSEisassociated
with fever. Some children with CSE associated with fever
have pre-existing neurological abnormalities, including
epilepsy, while others are previously neurologically nor-
mal. The latter group includes: (1) children in whom
their CSE were prolonged febrile seizures (i.e., febrile
CSE), defined as CSE in a previously neurologically nor-
mal child aged between 6 months and 5 years during a
febrile (temperature above 38◦
C) illness in the absence of
defined central nervous system (CNS) infection and (2)
children with acute symptomatic CSE due to CNS infec-
tions (Scott et al., 2003). Of note, the ILAE’s guidelines
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3. 1654 M. RASPALL-CHAURE ET AL.
TABLE 1. International League Against Epilepsy’s
recommended classification of status epilepticus according to
etiologies (Gastaut, 1983; ILAE Commission on Epidemiology
and Prognosis, 1993)
Acute symptomatic—Status epilepticus in a previously neurologically
normal child, within a week of an underlying etiology including CNS
infection, prolonged febrile seizures, encephalopathy, head trauma,
cerebrovascular disease, and metabolic or toxic derangements
Remote symptomatic—Status epilepticus in the absence of an
identified acute insult but with a history of a pre-existing CNS
abnormality more than 1 week before
Idiopathic epilepsy related—Status epilepticus that is not symptomatic
and occurred in children with a prior diagnosis of idiopathic epilepsy
or when the episode of status epilepticus is the second unprovoked
seizure that has led to a diagnosis of idiopathic epilepsy
Cryptogenic epilepsy related—Status epilepticus that is not
symptomatic and occurred in children with a prior diagnosis of
cryptogenic epilepsy or when the episode of SE is the second
unprovoked seizure that has led to a diagnosis of cryptogenic
epilepsy
Unclassified—Status epilepticus that cannot be classified into any
other group
establish that both should be classified as acute symp-
tomatic seizures (Table 1). This classification system,
which includes febrile CSE in the same category as CSE
due to an identified acute neurological insult, such as acute
bacterial meningitis, may be inappropriate for pediatric
epidemiological or outcome studies. It can be argued that
febrile CSE is clearly a separate entity with an overall fa-
vorable prognosis, and that studies that do not separate
febrile CSE and acute symptomatic CSE are likely to er-
roneously amplify the severity of outcome of febrile CSE
and conversely, dilute the severity of acute neurological
insults (Chin et al., 2006).
Thus a revised classification system of the etiologies of
CSE, with febrile CSE as a distinct category, may be more
applicable to pediatric epidemiological studies while re-
taining the flexibility to present data in keeping with the
current ILAE guidelines and thereby facilitate comparison
with other studies. Nonetheless, such a revised classifica-
tion would still have its limitations as accurate categoriza-
tion of individual cases may depend on the degree of inves-
tigation,theavailabilityofancillarytestsandclinicaldata.
INCIDENCE
One of the main strengths of epidemiological studies is
that in principle, they are free from the referral bias that
may occur in hospital based studies. The higher the de-
gree of case ascertainment the greater the likelihood that
results will be more applicable to the general population.
Case ascertainment poses a problem in studies on CSE.
The onset of CSE is not always witnessed and the time of
seizure termination is not always noted. Prospective stud-
ies demonstrate that when a detailed history is obtained,
the duration of seizure activity in children presenting at the
emergency department may be underestimated and thus,
cases of CSE may be missed (DeLorenzo et al., 1996;
Chin et al., 2006). Even when the diagnosis of CSE is
recognized, cases may still be missed because of lack of
reporting cases and problems associated with coding of di-
agnoses (Rahi and Dezateux, 1999). It is likely therefore
that epidemiological studies on CSE may miss cases un-
less sensitive screening methods are used and strategies
need to be employed to adjust crude estimates for de-
gree of ascertainment. Multiple sources of identification
of cases are superior to a single source and active surveil-
lance systems are better than passive systems (Knowles
et al., 2006).
Several population-based studies have addressed the in-
cidence of status epilepticus in Europe (Coeytaux et al.,
2000; Knake et al., 2001; Vignatelli et al., 2003) and in the
United States (DeLorenzo et al., 1996; Hesdorffer et al.,
1998; Wu et al., 2002), but with the exception of the most
recent one conducted in North London (Chin et al., 2006),
previously reported epidemiological studies of CSE have
been primarily or exclusively based on adult populations
and most have included all types of status epilepticus.
The estimated incidence of CSE in childhood ranges
from 10 to 38/100,000/year (Hesdorffer et al., 1998;
Coeytaux et al., 2000; Knake et al., 2001; Wu et al.,
2002; Vignatelli et al., 2003). The North London Convul-
sive Status Epilepticus in Childhood Surveillance Study
(NLSTEPSS) is the only study addressing CSE in a wholly
pediatric population. The incidence of CSE in childhood
in North London is 18–20/100,000/year, higher than the
4–6/100,000/year reported in epidemiological studies of
CSE in adult, excluding the elderly, populations (Chin
et al., 2006) (Table 2).
The incidence of CSE in childhood is highest among
children less than 1 year of age (51/100,000/year)
compared to those aged 1–4 (29/100,000/year), 5–9
(9/100,000/year), and 10–15 years (2/100,000/year). The
high incidence of CSE in children aged less than 1 year
is particularly marked in children with acute symptomatic
etiologies (Chin et al., 2006).
The higher frequency of CSE in very young and oth-
erwise neurologically normal children may be related not
only to the high proportion of acute symptomatic causes,
but also to an increased propensity for seizures of the im-
mature brain, which has been shown to be age depen-
dentinseveralexperimentalmodels(Ben-AriandHolmes,
2006). In addition to the lower seizure threshold and the
high incidence of neurological insults that may induce
CSE, there are several disorders that typically present
with seizures during early childhood (i.e., congenital brain
anomalies, genetic disorders, inborn errors of metabolism)
(Arzimanoglou et al., 2004) and these children may have
episodes of CSE as part of their epilepsy.
The role of gender, ethnicity, and socioeconomic
status on the incidence of CSE
In adults, males are twice as likely as females to have
an episode of CSE (Table 2) (Hesdorffer et al., 1998;
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4. EPIDEMIOLOGY OF STATUS EPILEPTICUS 1655
TABLE 2. Incidence of status epilepticus according to published population-based studies that have included children
Incidence rate Richmond Rochester Switzerland California North London
(per 100,000 persons per year) (DeLorenzo et al., 1996) (Hesdorffer et al., 1998) (Coeytaux et al., 2000) (Wu et al., 2002)a (Chin et al., 2006)b
Crude 41 18.3 9.9 6.8 14.5
Ascertainment adjusted 61 – – – 17–23
Age-adjusted – 18.3 10.3 – 13.3
Children 38 24 21 3.86 13.3
Adults 27 6 5 4.58 –
Elderly 86 62 15 14.6 –
Male:female – 2:1 1.5:1 1:1 1:1
Nonwhite:white 3:1 – – 2:1 2:1
Peak age <1, >60 <1, >65 <1, >60 <5, >60 <1
aRestricted to generalized convulsive status epilepticus.
bRestricted to convulsive status epilepticus.
Coeytaux et al., 2000; Knake et al., 2001). This gender
difference may be partly due to a higher incidence of
certain etiologies including cerebrovascular disease and
brain trauma in males. However, it may also reflect a
gender difference in seizure threshold (Moshe et al., 1995;
Standley et al., 1995) or a possible role of hormonal influ-
ences in the termination of seizures, which is supported
by the similar incidence observed in prepubertal boys and
girls. Ethnicity may also be an important determinant of
incidence of CSE given that a two- to threefold increase
in nonwhite populations is reported in the California and
Richmond studies (DeLorenzo et al., 1996; Wu et al.,
2002). The role of socioeconomic status on incidence
of CSE remains to be determined although preliminary
results of the North London study support the view that
this may have an important role (Chin et al., 2006b). If
the relationship between CSE and socioeconomic status
is confirmed then it is possible that the higher incidence
of CSE observed in the Richmond study attributed to the
racial composition of the population (57% black, 38%
white) is confounded by the socioeconomic composition
of Richmond. Indeed, Richmond, relative to the other
municipal localities of Virginia has the highest percent-
age of people living in poverty (21.4% compared to 6.2%)
(http://www.richmondgov.com/departments/budget/docs/
Map Poverty Data.pdf).
Epidemiological studies conducted in developing coun-
tries have found higher incidence rates of epilepsy than
in developed countries. Several factors such as infections
(malaria, neurocysticercosis), trauma, or limited medical
facilities are major determining factors for the increased
incidence (de Bittencourt et al., 1996), although ethnicity
and lower socioeconomic status may also play a role in
the observed increased incidence.
The role of genetic factors on the incidence of CSE
The higher incidence of CSE in non-white populations
suggests that differences in the incidence of CSE could be
genetically determined, particularly if the effect of ethnic-
ity is independent of socioeconomic status. This requires
evaluation in future studies. The role of genetic factors is
clear in some genetically determined epileptic syndromes
(i.e., Dravet syndrome and CSE with fever, ring chromo-
some 20, and non-CSE) (Augustijn et al., 2001; Nabbout
andDulac,2003),andtwinstudiessuggestthattheremight
also be some still unrecognized genetic predisposition to
CSE in many other individuals (Corey et al., 1998; Corey
et al., 2004).
Genetic backgrounds are being assessed for their po-
tential as modulators of adverse outcome, particularly de-
velopment of mesial temporal sclerosis (MTS), following
CSE and this may clarify whether CSE is a cause or symp-
tom of epilepsy (Haut et al., 2004). However, genetic asso-
ciation studies have given conflicting results. For example,
homozygosity for a low-expression allele for dynorphin
(an anticonvulsant peptide believed to be released dur-
ing seizures) has been associated with status epilepticus
and heterozygosity of this allele has been associated with
the presence of familial temporal lobe epilepsy. This may
imply a common genetic link between the allele, tempo-
ral lobe epilepsy, and status epilepticus (Stogmann et al.,
2002), although these results have not been replicated
in subsequent studies (Gambardella et al., 2003; Tilgen
et al., 2003). Genetic factors may also play a role on the
pathogenesis of CSE-related MTS. A higher frequency of
interleukin-1ß-511 polymorphism occurrence in Japanese
patients with temporal lobe epilepsy associated with MTS
has been reported, with the maximum increase being ob-
served in patients with a previous episode of febrile CSE
(Kanemoto et al., 2000; Kanemoto et al., 2003). Again,
subsequent studies examining the same polymorphism
carried out in American, Chinese, German, and Turkish
populations have failed to replicate these results (Heils
et al., 2000; Buono et al., 2001; Jin et al., 2003; Ozkara
et al., 2006), and it has been suggested that the initial
positive association between the interleukin-1ß-511 poly-
morphism may have arisen by chance (Tan et al., 2004).
Thus, the genetic basis underlying temporal lobe epilepsy
or MTS in patients with prior history of prolonged seizures
remains to be elucidated.
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5. 1656 M. RASPALL-CHAURE ET AL.
Place of CSE in the course of seizure disorders
Overall, between 10% and 20% of children with
epilepsy will have at least one episode of CSE during the
course of the disease, with most occurring in the first few
years of epilepsy onset (Sillanpaa and Shinnar, 2002; Berg
et al., 2004). Indeed, CSE is commonly seen as the first
manifestation of seizure disorders, especially in younger
children: between 62% and 88% of children with first-
ever episodes of CSE in population-based studies do not
have prior epilepsy (DeLorenzo et al., 1996; Chin et al.,
2006), although this proportion is age dependent. In young
children, the majority of cases of CSE occur in patients
with no history of seizures rather than as part of an estab-
lished seizure disorder and there are a higher proportion of
older children with prior seizures or epilepsy. It has been
speculated that, because the peak incidence of seizure dis-
orders is in the first years of life, younger children are
more likely to have CSE as their first seizure episode,
whereas older children are more likely to have CSE as
part of an already established seizure disorder. These dif-
ferences are not only explained by the age-dependent eti-
ological profile, as the proportion of children with prior
epilepsy is also different when the analysis is restricted to
children with cryptogenic or remote symptomatic epilepsy
(Shinnar et al., 1997). In North London, when CSE is as-
sociated with idiopathic/cryptogenic epilepsy, 62% have a
history of epilepsy or it is the second seizure (29%) or first
seizure (10%) leading to the diagnosis of epilepsy (Chin
et al., 2006).
A prospective study in which children with newly diag-
nosed epilepsy were recruited found that 9.1% of children
had one or more episodes of status epilepticus by the time
the diagnosis of epilepsy was made. Correlates of epilepsy
differed between provoked CSE (i.e., young age at onset
and nonidiopathic syndromes) and unprovoked CSE (i.e.,
focal seizures and craniotomy) (Berg et al., 1999b). Af-
ter a median follow-up of 8 years, subsequent CSE had
occurred in 7.2% of children without and in 32.1% of
those with CSE at diagnosis, i.e., those children who have
experienced an episode of CSE at, or soon after, diagno-
sis are much more likely to have another episode during
subsequent follow-up (Sillanpaa and Shinnar, 2002; Berg
et al., 2004). In addition, children with new onset seizures
largely fall into two groups; those that have short seizures
(<5 min in duration) and those that are likely to have 30
min seizures unless there is a clinical intervention (Shinnar
et al., 2001a). Thus, there might be a subgroup of children
with epilepsy who are predisposed to prolonged seizures.
Remote symptomatic epilepsy, age at onset (<1 year or
>60 years), and focal seizures were independent predic-
tors of CSE occurring at or after the diagnosis of epilepsy
in the Rochester population-based study (Hesdorffer et al.,
1995). Focusing on children in the remote symptomatic
group, a retrospective case–control hospital-based study
found that focal background abnormalities, secondarily
generalized focal seizures, first seizure as CSE, and gen-
eralized abnormalities on neuroimaging were indicators
of a higher risk of subsequent CSE (Novak et al., 1997).
Time trends in incidence of CSE
The Rochester study showed an increase in the over-
all incidence of status epilepticus across a 30 year pe-
riod (Logroscino et al., 2001). The study included mainly
adults and the reported increase in incidence was largely
due to the increase in myoclonic status epilepticus after
cardiac arrest although methodological issues (i.e., bet-
ter recognition of more subtle forms of status epilepti-
cus) could also have accounted for the apparently time-
dependent increase of incidence. When only generalized
CSE is considered, two population-based studies have
shown a decline in its incidence (Logroscino et al., 2001;
Wu et al., 2002).
There are no published studies specifically addressing
time trends of incidence of CSE in children. There is
some evidence that the incidence of epilepsy over time
has decreased in children (Hauser et al., 1993; Sander and
Shorvon, 1996; Everitt and Sander, 1998). Whether these
results also apply to incidence of CSE in children remains
to be shown. More prolonged survival of children with
severe underlying neurological conditions may favor an
increase in the incidence of pediatric CSE, while the im-
provement of perinatal and overall medical care, including
earlier treatment of prolonged seizures, may have reduced
the incidence of established CSE.
The effect of early treatment on incidence
In more than three-quarters of children with a first-
ever episode of CSE, the episode starts in the commu-
nity. Although prehospital treatment is widely recom-
mended, in practice the use of such treatment may be
suboptimal. Many children are either not treated or are
treated with doses that are below those suggested in guide-
lines such as that produced by the APLS group based
in the United Kingdom. A retrospective hospital-based
study emphasized that inappropriate treatment, including
no prehospital treatment or excessive administration of
benzodiazepines, contributes to the need for intensive care
(Chin et al., 2004b).
A population-based study conducted in Bologna, Italy,
reported a mortality rate of 39% in adults with all types
of status epilepticus (Vignatelli et al., 2003). The authors
hypothesized that this extremely high case fatality rate
might be in part secondary to inadequate management of
status epilepticus, i.e., administration of prehospital treat-
ment in only 17% of cases, lack of local hospital proto-
cols, and use of diazepam as first-line drug (instead of
lorazepam). In contrast, the population-based study con-
ducted in Switzerland reported a much lower overall case
fatality rate at 7.6%, and this was in part attributed to
initiation of treatment in the prehospital setting in almost
60% of patients (Coeytaux et al., 2000). Seizure clustering
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6. EPIDEMIOLOGY OF STATUS EPILEPTICUS 1657
is also associated with an increased risk of CSE, and thus
rapid treatment of seizure clusters has also been suggested
as a way of reducing the incidence of CSE (Haut et al.,
2005).
It is possible that early pharmacological intervention
leads to termination of seizures with smaller doses than
would be required if seizures were allowed to progress
(Mazarati et al., 1998). Experimental data show time-
dependent loss of synaptic GABAA receptors, and thus of
GABA-mediatedinhibition,whichcorrelateswiththepro-
gressive pharmacological resistance to GABAergic med-
ication observed in refractory status epilepticus (Kapur
et al., 1989), further supporting the view that treatment
should commence in the prehospital setting.
Several studies have reported on the efficacy and safety
of transmucosal benzodiazepines for the acute manage-
ment of seizures in children and it has been suggested that
their use in the prehospital setting may improve the out-
come (Scott et al., 1999; Lahat et al., 2000; McIntyre et al.,
2005). It can be hypothesized that the improved outcome
may be achieved not only by decreasing the duration of
CSE and facilitating its subsequent management in the
hospital setting, but also by an actual decrease in the inci-
dence of CSE (assuming a 30 min definition). Future epi-
demiological studies should aim to investigate whether the
extensive implementation of prehospital treatment does
not only improve the outcome but also reduces the inci-
dence of established CSE in children.
It can be concluded that the incidence of CSE is mainly
a function of age, which in turn may reflect differences
in maturation of the developing brain and in the etiologi-
cal profile of particular age groups or geographical areas.
Treatment facilities, gender, ethnicity, and genetic and so-
cioeconomic factors also seem to influence the epidemiol-
ogy of CSE. Thus, the incidence in populations will vary
depending upon all the above factors. Studies to identify
specific genetic or socioeconomic factors associated with
CSE are required to pinpoint potential targets for primary
prevention of CSE.
SEIZURE TYPE: ONSET, CHARACTER,
AND DURATION
The reported frequencies of the initiating seizure type
in pediatric CSE are discordant. The Richmond study re-
ported that focal seizures, defined on clinical evaluation,
were the initiating seizure type in nearly two-thirds of
cases, but was the initiating seizure type in only one-third
of children in the North London study (DeLorenzo et al.,
1996; Chin et al., 2006). However, both studies showed
a high rate of secondary generalization, with generalized
tonic–clonic CSE being the most common final seizure
type.
Tonic and purely clonic seizures are uncommon. The
incidence of tonic CSE among children with first-ever
episodes peaks in children less than a year, especially
in those with acute symptomatic etiologies (Chin et al.,
2006). In hospital-based studies, tonic CSE is mainly re-
ported in children and adolescents with previous epilepsy,
particularly in patients with Lennox–Gastaut syndrome
(Arzimanoglou et al., 2004). Purely clonic seizures are
reported in less than 5% of children in population-based
studies (Coeytaux et al., 2000; Chin et al., 2006). It has
been argued that there are a proportion of prolonged
seizuresasdocumentedclinicallythatmaybenonepileptic
events (Stephenson, 2006). All studies assessing seizure
types may therefore contain such patients.
Not all seizures are continuous in their nature, i.e., there
are a proportion of seizures that appear to terminate but the
patient does not recover consciousness and subsequently
has further clinical events. This is defined as intermittent
CSE. The incidence of intermittent and continuous CSE in
children is similar amongst all age and etiological groups
(Chin et al., 2006). It has been shown that continuous CSE
is associated with higher mortality than intermittent CSE
in adults even after controlling for CSE duration, but this
may not be the case in children (Waterhouse et al., 1999).
In addition to offering prompt medical treatment,
seizure duration may also depend upon etiology and age.
In the North London study, 60% of children had CSE last-
ing longer than 1 h with no differences in the duration
of CSE noted between different etiological groups (Chin
et al., 2006). This finding is contrary to those from some
hospital-based studies that report acute symptomatic CSE
to be associated with a longer duration of CSE (Maytal
et al., 1989; Eriksson and Koivikko, 1997; Tabarki et al.,
2001). In the Rochester study the risk of CSE of longer
duration was greatest for infants and for the elderly. Addi-
tionally, among cases with first-ever acute symptomatic
seizures and unprovoked seizures, the proportion with
CSE was increased in infancy and in the elderly, thus sug-
gesting that age may also modulate duration (Hesdorffer
et al., 1998).
ETIOLOGY
The cause of CSE varies across age groups and there is
a strong correlation between age at the time of CSE and
etiology: in children younger than 2 years, febrile CSE and
acute symptomatic etiologies are most common, whereas
cryptogenic and remote symptomatic etiologies are more
common in the older children (Shinnar et al., 1997).
Several population-based studies have reported on the
etiological distribution of CSE in childhood (Table 3). Al-
though most have been conducted after the ILAE’s pub-
lished guidelines for epidemiologic studies in epilepsy
(Commission on Epidemiology and Prognosis, 1993;
ILAE Commission Report, 1997), differences in etiolog-
ical criteria have resulted in discordant results. As pre-
viously discussed, according to the ILAE’s guidelines
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7. 1658 M. RASPALL-CHAURE ET AL.
TABLE 3. Etiology of status epilepticus according to
population-based incidence studies that included children (the
Californian study is excluded because proportional
contributions of etiologies from their study could not be
determined)
North
Richmond Rochester Switzerland London
Etiology (n = 29) (n = 69) (n = 64) (n = 176)
Febrile a 23% b 32%
Acute symptomatic 52% 46% 66% 17%
Remote symptomatic 39% 18% 25% 16%
Idiopathic/ 5% 13% 9% 19%
cryptogenic/
unknown
Acute on remote – – – 16%
aFebrile CSE was included in the acute symptomatic group.
bData for febrile CSE were not provided separately but 58% of acute
symptomaticseizuresinchildren<5yearsoldwerereportedtobefebrile.
febrile seizures should be classified as acute symptomatic
seizures. This was the criterion used in the Richmond
and Swiss studies, in which children with febrile CSE
were included within the acute symptomatic group (De-
Lorenzo et al., 1996; Coeytaux et al., 2000). However,
in the Rochester and North London studies, children with
FSE were classified and analyzed separately on both prag-
matic grounds and because of the probable lack of direct
CNS involvement in febrile seizures (Hesdorffer et al.,
1998; Chin et al., 2006).
Febrile CSE, which occurs in 5% of patients experienc-
ing febrile seizures (Annegers et al., 1987; Verity et al.,
1993), is the most common type of CSE in childhood, ac-
counting for at least one-third of all cases. Although by
definition, febrile seizure is restricted to children younger
than 6 years, the age-adjusted incidence of febrile CSE is
still greater than that for each of the other causes of CSE
across the whole of childhood (Chin et al., 2006).
In a subgroup analysis of 95 children from the North
London study with first-ever episodes of CSE associated
with fever, 12% had acute bacterial meningitis and 8% had
aviralCNSinfectioncomparedwitharateof1–2%inchil-
dren with a short febrile seizure (Chin et al., 2005). The
remaining children had febrile CSE (59%) or had a pre-
vious neurological abnormality with a febrile intercurrent
illness (22%). Previously neurologically normal children
with first-ever CSE associated with fever were seven times
more likely to have an acute CNS infection compared to
children with first-ever CSE associated with fever but with
a preexisting neurological abnormality (Chin et al., 2006).
Thus, CNS infection should be carefully ruled out in chil-
dren with fever and CSE, especially in those who are pre-
viously neurologically normal (Chin et al., 2005).
Each of the other etiologies (i.e., idiopathic/cry-
ptogenic, acute symptomatic, remote symptomatic, and
progressive) account for 15–20% of total. Low antiepilep-
tic drug level was reported as the cause of 21% of CSE in
the Richmond study, but was only observed in one child
in the North London study; the much lower proportion of
children with prior epilepsy in the latter study may ac-
count for the difference (DeLorenzo et al., 1996; Chin
et al., 2006).
More than 40% of children with first-ever CSE in
the North London study were previously neurologically
abnormal (i.e., abnormal neurodevelopment, history of
epilepsy or neurological deficits). This figure is similar
to previous studies and suggests that neurologically ab-
normal children are more susceptible to develop seizures
in general and CSE in particular. The proportion of previ-
ously neurologically abnormal children is age dependent:
21% of children younger than 2 years are neurologically
abnormal compared to 43% of children aged 2–5 years
and 59% of children older than 5 years (Shinnar et al.,
1997).
OUTCOME
Much of the importance attached to CSE is based upon
its morbidity and mortality. Although there is an increase
in morbidity and mortality in CSE this seems to be mostly
related to etiology and is less in children than in adults.
The role of the epileptic discharges in generating adverse
outcomes requires further investigation and there is still
much controversy as to whether age, duration, or treatment
modifies the outcome of CSE. Much of the controversy
arises from methodological differences of studies address-
ing this topic (Hauser, 1983; Logroscino and Hesdorffer,
2005). The impact of nonbiological variables on reported
outcomes of pediatric CSE was investigated in a recent
systematic review that concluded that prospective design
and overall better methodological quality were associated
with better outcome (Raspall-Chaure et al., 2006).
Mortality
Reported short-term mortality associated with pediatric
CSE (i.e., death during hospital admission or within the
first 30 to 60 days of onset of CSE) in population-based
studies is 2.7–5.2% (Verity et al., 1993; DeLorenzo et al.,
1996; Waterhouse et al., 1999; Chin et al., 2006). In the
North London study, children with acute or remote symp-
tomatic CSE, in similar proportions (10% and 18%, re-
spectively), were associated with the highest mortality
during hospitalization (Chin et al., 2006); no deaths were
observed in the cryptogenic or febrile groups, suggest-
ing that CSE itself plays little role in short-term mortality
(Maytal et al., 1989; Logroscino et al., 1997; Garzon et al.,
2003).
Age and duration of CSE may also affect mortality al-
though their effects need further clarification. The higher
mortality reported in younger children in some studies
may only reflect the higher proportion of acute symp-
tomatic cases in this age group (Aicardi and Chevrie,
1970;Logroscinoetal.,1997).TheRichmondstudy,using
Epilepsia, Vol. 48, No. 9, 2007

8. EPIDEMIOLOGY OF STATUS EPILEPTICUS 1659
CSE lasting <1 h as the reference group, found longer
duration to be associated with a higher 30-day mortality
(Towne et al., 1994). In contrast, duration of CSE was
not a predictor of short-term mortality in the Rochester
study, even after restriction of the analysis to acute symp-
tomatic causes: no significant differences were observed
when individuals with CSE lasting less than 2 h (reference
group) were compared to those with CSE lasting 2–24 h or
>24h (Logroscino et al., 1997). In a retrospective study
conducted over a 11 year period in Dakar, Senegal, the
mean time between the onset of symptoms and the ini-
tiation of treatment was 16.6 h. Despite the delay in the
initiation of treatment, overall mortality (24.8%) was sim-
ilar to that observed in Richmond or Rochester, which may
suggest that outcome is not significantly influenced by the
duration of the episode of CSE (Mbodj et al., 2000). How-
ever, none of these studies were carried out exclusively in
pediatric populations and therefore it remains uncertain
whether duration of CSE influences mortality in children.
Long-term mortality data after a first-ever episode of
CSE are variable, with estimates ranging from 5.4% to
17%. At 10 years follow-up, mortality was 3% for 30-
day survivors aged 1–19 years and 16% for infants <1
year in the Rochester study. As with short-term mortal-
ity, a higher mortality was seen in symptomatic CSE,
but not with cryptogenic or idiopathic CSE (Logroscino
et al., 2002). Another population-based study reporting 24
deaths among 150 patients with childhood-onset epilepsy
after a follow-up of 30 years did not identify a higher
mortality in those with prior CSE (Sillanpaa and Shin-
nar, 2002). These population-based studies suggest that
CSE itself may not have a significant impact on long-
term mortality in childhood-onset epilepsy. To some ex-
tent these results may be comparable to epidemiological
studies on mortality of epilepsy showing no significant
increase in mortality in people with idiopathic epilepsy
(Forsgren et al., 2005).
To assess the contribution of CSE itself to mortality it
is necessary to either study idiopathic–cryptogenic cases
or to compare the mortality of people with first-ever CSE
and an underlying condition to the mortality of individuals
from the same population with the underlying condition
but without CSE stratified by severity of the underlying
condition (Logroscino and Hesdorffer, 2005). Although
this has already been carried out in studies in adults with
stroke and status epilepticus (showing that there is a syner-
gistic effect on mortality) (Waterhouse et al., 1998; Knake
et al., 2006), we are not aware of any such study in chil-
dren.
Morbidity
In addition to epilepsy, focal neurological deficits, cog-
nitive impairment and behavioral problems can be associ-
ated with CSE although consistent specific risk factors for
each of these adverse outcomes are not reported (Raspall-
Chaure et al., 2006).
Etiology is also the main determinant of morbidity. The
poorest outcome is observed in acute symptomatic CSE,
which is followed by new neurological dysfunction in
>20% of cases. In the absence of an acute or progressive
neurological disorder, morbidity of CSE is low, and <15%
of children with febrile CSE and unprovoked CSE de-
velop new neurological deficits attributable to CSE (May-
tal et al., 1989; Eriksson and Koivikko, 1997; Barnard and
Wirrell, 1999; Shinnar et al., 2001b). However, low power
and inadequate methodology might have underestimated
the incidence of minor sequela in most of the studies. This
is especially true for population-based studies on CSE as
none have applied formal neurocognitive assessments.
A recent hospital-based study in adults with epilepsy
showed no cognitive deterioration after an episode of sta-
tus epilepticus (6 CSE, 9 non-CSE), as demonstrated by
the Wechsler Adult Intelligence Scale—Revised before
and after the episode (Adachi et al., 2005). Despite previ-
ous evidence to the contrary (Dodrill and Wilensky, 1990)
andlackofsimilarstudiesinchildren,theseresultssuggest
that patients with earlier epilepsy and no acute medical ill-
nesses do not have long-term cognitive deficits from CSE
itself.
Other factors that are reported to influence the out-
come are longer seizure duration and younger age at on-
set. As with mortality, the poorer outcome observed in
refractory or more prolonged CSE and in young children
might be only explained by the greater incidence of acute
symptomatic CSE in these groups (Raspall-Chaure et al.,
2006).
Recurrence
A significant proportion (16%) of children with first-
ever CSE will have a recurrence within a year (Chin et al.,
2006). The risk is mainly determined by the etiology, and
it is highest in the remote symptomatic (44%) and progres-
sive (67%) groups (Shinnar et al., 1992). Among children
with first-ever episodes of febrile CSE, 17% will have an-
other episode within a year. This contrasts with another
population-based study in which no recurrences were ob-
served (Verity et al., 1993). Children with existing neuro-
logical abnormalities are 3–23 times more likely to have a
recurrence than those who are previously neurologically
normal (Shinnar et al., 1992; Chin et al., 2006). The me-
dian interval from first-ever CSE to first recurrence is 25
days (95% CI 0–78) and there is no difference in the mean
interval from first-ever CSE to first recurrence between
children with and without previous neurological abnor-
malities (Chin et al., 2006). The risk of recurrence is at its
maximum during the first year after the episode of CSE,
butitdoesnotdisappearafterwards.Infact,thehighestrisk
of recurrence has been reported in two population-based
studies with 10 and 30 years of follow-up (Verity et al.,
Epilepsia, Vol. 48, No. 9, 2007

9. 1660 M. RASPALL-CHAURE ET AL.
1993; Sillanpaa and Shinnar, 2002). Thus, differences in
reported risk of recurrence might depend not only on the
etiological distribution of the series, but also on the length
of follow-up.
Subsequent epilepsy
It remains uncertain whether epilepsy occurs as a result
of an episode of CSE or if CSE and subsequent epilepsy
are both the result of a common brain insult. The overall
risk of subsequent unprovoked seizures 2 years follow-
ing a first-ever unprovoked episode of CSE is 25–40% in
hospital-based studies (Maytal et al., 1989; Eriksson and
Koivikko, 1997), which is similar to the 37% reported risk
following a brief first unprovoked seizure (Hauser et al.,
1982; Berg and Shinnar, 1991). In contrast, more than 50%
of children with acute symptomatic etiologies or previous
neurological abnormalities will develop epilepsy (Verity
et al., 1993; Sahin et al., 2001; Kramer et al., 2005).
Experimental studies suggest that prolonged febrile
seizuresintheimmaturebrainproducepersistentenhance-
ment in hippocampal excitability, which may facilitate the
subsequent development of epilepsy if the animal is ex-
posed to other epileptogenic insults (Dube et al., 2000).
Clinical data on epilepsy following febrile CSE are con-
troversial and much of the variability of estimates arises
from differences in inclusion criteria. Studies that include
children with prior neurological abnormalities reveal that,
when compared to brief febrile seizures, the risk follow-
ing febrile CSE is not different in neurologically normal
children but it is significantly increased (38%) in those
with prior neurological abnormalities. Nelson and Ellen-
berg (1978) reported that 4.1% of children with first febrile
seizure as febrile CSE developed epilepsy, which is signif-
icantly higher than in the normal population, but did not
reach statistical significance when compared to children
who had brief febrile seizures. In contrast, Verity et al.
(1993) found a significantly greater risk of developing
afebrile seizures in children with febrile CSE compared
with children with brief febrile seizures (21% vs. 3.4%;
x2
= 9.77; p<0.005).
It has long been hypothesized that CSE (and in par-
ticular febrile CSE) can cause MTS and associated tem-
poral lobe epilepsy. Retrospective studies from tertiary
epilepsy centers highlight this association, with a history
of febrile CSE being present in 35–63% of patients with
MTS (Cendes et al., 1993; Murakami et al., 1996). How-
ever, neither population-based nor prospective hospital-
based studies report a significant association between
CSE in childhood and subsequent MTS (Camfield et al.,
1994; Berg et al., 1999a; Tarkka et al., 2003). Although
febrile CSE has been associated with increased incidence
of subsequent partial seizures, the structural bases for
these seizures has not been characterized (Annegers et al.,
1987). There are, however, studies that show evidence for
an acute hippocampal insult following febrile CSE in chil-
dren and this may represent the first part of a causative
pathophysiological sequence linking febrile CSE to MTS
(VanLandingham et al., 1998; Scott et al., 2002; Scott
et al., 2003).
The risk of seizure recurrence is highest during the first
year following CSE and tends to decrease with increas-
ing interval from the index seizure. However, the positive
correlation between reported incidence of seizure recur-
rence and length of follow-up suggests that the risk of
subsequent epilepsy may remain for many years after the
initial episode of CSE (Raspall-Chaure et al., 2006). The
impact of early treatment on the prevention or course of
epilepsy remains largely unknown, and the current recom-
mendation of not starting long-term treatment after a first
unprovoked CSE is based on the reported low impact of
CSE on the risk of recurrence.
SUMMARY AND FUTURE DIRECTIONS
The population-based studies that have been conducted
in Europe and the United States have clarified the inci-
denceofCSEinchildrenandhaveidentifiedsomeputative
risk or modifying factors for CSE in developed countries,
i.e., age, ethnicity, genetics, and socioeconomic status.
However, many of the objectives for “future epidemiolog-
ical studies” suggested by the ILAE in order to improve
our knowledge on the epidemiology of seizure disorders
have not been met yet (ILAE Commission Report, 1997).
There is still a need for further studies with appropriate
methodology to answer some as yet unclarified questions,
i.e., (a) the magnitude of geographic variations in inci-
dence, (b) the relative contribution of different etiological
profiles, genetic background, and socioeconomic status to
these variations, (c) the incidence rates specific for each
type of CSE, and (d) the effect of widespread implemen-
tation of prehospital treatment for prolonged seizures on
incidence rates. As recommended by the ILAE, studies
should ideally be population based and prospective, and
all rates should be age adjusted.
Although long-term prospective population-based and
appropriately conducted hospital-based studies consis-
tently report that etiology is the main determinant of
outcome, the relationship of CSE with MTS or sub-
tle neurocognitive dysfunction, and the effect of age at
CSE, seizure duration, or treatment on outcome have
not yet been clarified. Future studies controlling for the
severity of the underlying etiology should aim to eluci-
date these points in order to determine how much re-
source should be put into the prevention and treatment
of CSE.
Acknowledgments: Miquel Raspall-Chaure is the recipient
of a research fellowship from The National Centre for Young
People with Epilepsy, Lingfield, UK. Funding sources played no
part in the preparation of this review or in the decision to submit
it for publication.
Epilepsia, Vol. 48, No. 9, 2007

10. EPIDEMIOLOGY OF STATUS EPILEPTICUS 1661
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